Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:5].[C:23](Cl)(Cl)=[S:24].C(N(CC)CC)C>C1(C)C=CC=CC=1.COC(C)(C)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]1[O:5][C:23](=[S:24])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:6]=1
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1F
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: Fc1cccc(F)c1-c1nn(-c2ccccc2C(F)(F)F)c(=S)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.79 g (15 mmol) of 2,6-difluoro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide in 30 ml of toluene are treated with 1.98 g (17 mmol) of thiophosgene and the reaction mixture is heated at the reflux temperature for 5 hours. 4.8 ml (35 mmol) of triethylamine are then added dropwise at 45° C. while cooling and, after cooling, the mixture is stirred at room temperature for about 1 hour. The mixture is subsequently taken up in 100 ml of tert.butyl methyl ether and the solution is washed in each case once with dilute, ice-cold sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is purified by chromatography using acetone/n-hexane (1:4) as the eluent and crystallized from diisopropyl ether/n-hexane. In this manner there is obtained 5-(2,6-difluorophenyl)-3-(α,α,α-trifluoro-o-tolyl)-1,3,4-oxadiazole-2(3H) -thione as a white crystallizate, m.p. 128°-130° C.; mass spectrum: 358(58), 298(15 ), 289(17), 159(100).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]>[Fe].C(O)(=O)C>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([N+:13]([O-:15])=[O:14])[C:2]=1[Cl:1])[C:6]#[N:7].[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH2:10])[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1cc(N)c(Cl)c(N)c1
Product: N#Cc1cc(N)c(Cl)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A 3-neck round bottom flask was equipped with a condenser. The flask was loaded with 4-chloro-3,5-dinitrobenzonitrile (4.5 g, 19.18 mmol) and acetic acid (60 mL). The solution was heated to 110° C. Iron (powder) (2.5 g, 44.8 mmol) was added slowly (in three portions), saw bubbling and also color changed to dark red. The mixture was stirred vigorously for 2 h at 110° C. LC-MS indicated desired monoamine and diamine. Then it was cooled to room temperature and diluted with DCM and saturated aqueous sodium bicarbonate solution was slowly added to neutralize. After separating the layers, the aqueous layer was further extracted with DCM. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Purification via flash chromatography (0-20% EtOAc in DCM, 120 g) gave 3-amino-4-chloro-5-nitrobenzonitrile (1.8 g) and 3,5-diamino-4-chlorobenzonitrile (1 g) as bright yellow solid and brown solid respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[Se:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:26]2[CH:21]([CH:22]3[O:27][CH:25]2[CH2:24][CH2:23]3)[C:20](=[O:28])[CH:19]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[Se:9][C:10]([CH2:13][O:14][C:18]3[CH:26]4[CH:21]([CH:22]5[O:27][CH:25]4[CH2:24][CH2:23]5)[C:20](=[O:28])[CH:19]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1cnc(-c2ccc(Cl)cc2)[se]1
Reactant: O=C1C=C(Cl)C2C3CCC(O3)C12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(OCc2cnc(-c3ccc(Cl)cc3)[se]2)C2C3CCC(O3)C12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
To a solution of [2-(4-chlorophenyl)selenazol-5-yl]methanol (300 mg, 1.1 mmol) in dry tetrahydrofuran (5 ml) is added, in one portion, sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol). The reaction mixture is stirred for 5 minutes at room temperature and 5-chloro-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (203 mg, 1.1 mmol) is added in one-portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 5-[2-(4-chloro-phenyl)-selenazol-5-ylmethoxy]-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (360 mg).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[C:12]([O:16][C:17]([N:19]1[CH2:27][C:26]2[CH:25]=[N:24][C:23](SC)=[N:22][C:21]=2[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[S:30]([O-:33])([O-])=[O:31].[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:27][C:26]2[CH:25]=[N:24][C:23]([S:30]([CH3:2])(=[O:33])=[O:31])=[N:22][C:21]=2[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(n1)CN(C(=O)OC(C)(C)C)C2
Reactant: O=S([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cnc(S(C)(=O)=O)nc2C1
Reaction time: 5 h

Procedure:
m-Chloroperbenzoic acid (1.99 g) was added to a dichloromethane solution (20 ml) of 6-(tert-butoxy-carbonyl)-5,7-dihydro-2-methylthiopyrrolo[3,4-d]-pyrimidine (1.08 g) under ice cooling, and the mixture was stirred for 5 hours. A saturated aqueous solution of sodium sulfite, a saturated aqueous solution of sodium hydrogen carbonate and dichloromethane were added to separate an organic layer. The organic layer was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, and powder deposited was collected by filtration to obtain the title compound (1.09 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[Na+].[SH:31][CH2:32][CH2:33][S:34]([O-:37])(=[O:36])=[O:35].COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:31][CH2:32][CH2:33][S:34]([OH:37])(=[O:36])=[O:35])[CH:15]=1
Reactant: O=S(=O)([O-])CCS
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CCl)c1
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CSCCS(=O)(=O)O)c1
Temperature: 40 °C
Reaction time: 96 h
Yield: 46.1 %

Procedure:
Subsequently, methyl 5-chloro-2-[3-(chloromethyl)benzoyl]aminobenzoate (1.8 g) was dissolved in anhydrous methylene chloride. Triethylamine (1.5 ml) and 2-mercaptoethanesulfonic acid sodium salt (compound B′) (1.3 g) were added to the solution at room temperature, and the mixture was stirred at 40° C. for 4 days. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated. The residue was purified by column chromatography on silica gel to give 5-chloro-2-[3-(2-sulfo-ethylsulfanylmethyl)-benzoylamino]-benzoic acid methyl ester (1.08 go yield 46.1%) as a useful intermediate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:29][CH:30]5[CH2:35][NH:34][CH2:33][CH:31]5[N:32]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:29][CH:30]5[CH2:35][N:34]([C:36](=[O:38])[CH3:37])[CH2:33][CH:31]5[N:32]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6CNCC6O5)cc34)cc2C)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CC2N=C(Nc3ccc4ncnc(Nc5ccc(Oc6ccc(C)nc6)c(C)c5)c4c3)OC2C1

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazol-5-yl)-ethanone is prepared from N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride. MS APCI (+) m/z 510 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.71 (m, 2H), 7.63 (m, 2H), 7.28 (m, 2H), 7.00 (d, 1H), 5.28 (m, 1H), 4.89 (m, 1H), 4.15 (d, 0.5H), 4.03 (m, 1H), 3.84 (d, 0.5H), 3.75 (m, 1H), 3.47 (m, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.09 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH2:18]([CH2:20][NH2:21])[OH:19]>>[ClH:1].[C:12]1([C:4]2[CH:3]=[C:2]([NH:21][CH2:20][CH2:18][OH:19])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCO
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Product: Cl
Product: OCCNc1cc(-c2ccccc2)nc2ccccc12

Procedure:
The title compound, m.p. 258-260° C., MS: m/e=264 (M+), was prepared from 4-chloro-2-phenyl-quinoline and ethanolamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.[OH-:10].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N+:3]=1[O-:10]
Reactant: [OH-]
Reactant: CCc1cccc(Br)n1
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1cccc(Br)[n+]1[O-]
Temperature: 50 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-6-ethyl-pyridine (15.4 g, 82.8 mmol) (S. G. Davies and M. R. Shipton, J. Chem. Soc., Perkin Trans. 1, 1991, 3, 501) in acetic acid (15 ml) peracetic acid (26 ml of a 39%) solution) was added maintaining T<50° C. After completed addition the mixture was stirred at 50° C. for 5 hr and then cooled to rt. Crushed ice (40 g) was added and the mixture was made basic (pH 12) using 40% KOH solution. After extraction with CHCl3 (6×60 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 20.0 g (>100%) of the title compound, MS: m/e=201 (M+) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[C:29]([S@:33]([NH2:35])=[O:34])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20]/[C:21](=[N:35]\[S@@:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:34])/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N(CCC/C(=N\[S@](=O)C(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Yield: 51 %

Procedure:
(S)-tert-butyl 1-(4-bromophenyl)ethyl(4-oxo-4-phenylbutyl)carbamate (3.14 g, 7.04 mmol), (R)-t-Butylsulfinamide, Ti(OEt)4 (125 μL, 1.5 equiv) were mixed with dry THF (80 mL) and heated at reflux for overnight. LC-MS found most of starting material was consumed. The mixture was diluted with ether (200 mL), washed with water (50 mL), brine (30 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120-g silica gel cartridge, eluted with a 10˜35% EtOAc in hexanes gradient, to afford tert-butyl (S)-1-(4-bromophenyl)ethyl((E)-4-((R)-tert-butylsulfinylimino)-4-phenylbutyl)carbamate (1.97 g, 51%) product and recovered starting material (0.72 g). LC-MS Method 1 tR=2.43 min, m/z 549, 551 (M+1)
Reaction SMILES: [N+:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([Br:11])(=O)[CH3:9].[OH-].[Na+]>>[Br:11][C:8]1[C:3]([CH3:4])=[CH:2][N+:1]([O-:7])=[C:6]([CH3:5])[CH:9]=1
Reactant: [O-][n+]1ccccc1
Reactant: CC(=O)Br
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)cc1Br
Temperature: 55 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A portion of the pyridine-N-oxide (106.4 g, 0.633 mol) was added slowly to 300 g of acetyl bromide at a rate that maintained the reaction temperature at 20°-30° C. (modification of procedure described in Ochiai, J. Org. Chem, 18, 549(1953)). After the addition was complete, the reaction was heated to 55° C. and left to stir overnight. The reaction mixture was cooled to room temperature and then slowly poured over ice. The mixture was slowly basified with 10M sodium hydroxide and extracted with chloroform. The chloroform extract was dried over sodium sulfate and then concentrated to dryness to give 119.2 g (93%) of 4-bromo-2,5-dimethylpyridine-N-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.I[C:38]1[CH:39]=[C:40]([C:44]2[NH:45][CH2:46][CH2:47][N:48]=2)[CH:41]=[CH:42][CH:43]=1.ClCCl.C(=O)(O)[O-:53].[Na+]>C(#N)C>[NH:48]1[CH2:47][CH2:46][N:45]=[C:44]1[C:40]1[CH:39]=[C:38]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][NH:11][C:12]3=[N:13][CH:14]=2)[CH:43]=[CH:42][CH:41]=1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[C:40]([C:44]4([OH:53])[NH:45][CH2:46][CH2:47][NH:48]4)[CH:41]=[CH:42][CH:43]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Ic1cccc(C2=NCCN2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C4(O)NCCN4)c3)cc12
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C4=NCCN4)c3)cc12

Procedure:
A mixture of the 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (43 mg, 0.085 mmol), 2-(3-Iodo-phenyl)-4,5-dihydro-1H-imidazole (34.7 mg, 0.128 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (3.1 mg, 4.2 μmol) in 0.8 ml acetonitrile/0.8 ml 2N sodium carbonate irradiated in a Personal Chemistry Optimizer at 135° C. for 20 minutes. The crude reaction mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-[3-(4,5-Dihydro-1H-imidazol-2-yl)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (11.2 mg, MS: MS: m/z 369.1 [MH+]) and 2-{3-[3-(2-Methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-imidazolidin-2-ol (13.2 mg, m/z 387.1 [MH+]), both as green solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:13])[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([O:17]CC)=[O:16])=[CH:4]1)[CH3:2].O.O.[OH-].[Li+].Cl>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:13])[CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(I)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2ccc(I)cc21
Reaction time: 3 h
Yield: 94.7 %

Procedure:
A suspension of 2.4 g of ethyl 1-ethyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 13 g)) in 20 ml of ethanol and 6 ml of water is treated at 0° with 325 mg of lithium hydroxide monohydrate. After 3 hrs. the reaction mixture is acidified with 25% aqueous hydrochloric acid. The precipitated substance is filtered off under suction, washed with 20 ml of water, 20 ml of ethanol and 20 ml of ether and dried. 2.1 g (94%) of 1-ethyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid are obtained as a colourless solid. M.p. 237°-238°.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([P:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:30][OH:31].C[O-].[Na+].Cl>CO>[OH:31][NH:30][C:3](=[O:2])[CH2:4][N:5]([P:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CN(CCc1ccccc1)P(=O)(c1ccccc1)c1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CN(CCc1ccccc1)P(=O)(c1ccccc1)c1ccccc1)NO
Reaction time: 16 h
Yield: 25.7 %

Procedure:
N-(Diphenyl phosphinyl)-N-(2-phenylethyl)glycine methyl ester (160 mg, 0.41 mmol) is dissolved in methanol (2.5 mL). To this is added hydroxylamine hydrochloride (57 mg, 0.81 mmol), followed by a 2 mmol of a 25% methanolic solution of sodium methoxide. The reaction is stirred for 16 hours, neutralized with 1N hydrochloric acid and concentrated. The crude product is purified by silica gel flash chromatography to give 41.6 mg (26%) of N-hydroxy-2-[[diphenylphosphinyl](2-phenylethyl)-amino]-acetamide as a colorless solid: MS-IS m/z 395 [M+H]+, 417 [M+Na]+, 433 [M+K]+. (R1 =phenyl ethyl, R2 =H, R3 =phenyl, R4 =phenyl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:11][C:12]1[CH:13]=[CH:14][C:15]2[S:19][CH2:18][CH2:17][C:16]=2[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]3[S:19][CH2:18][CH2:17][C:16]=3[CH:20]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Oc1ccc2c(c1)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1Oc1ccc2c(c1)CCS2
Temperature: 90 °C
Yield: 61.8 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol), 5-hydroxy-2,3-dihydrobenzothiophene (prepared as described in Synth. Commun. 1991, 21, 959-964) (808 mg, 5.31 mmol) and K2CO3 (1.47 g, 10.6 mmol) in DMF (5 mL) was heated at 90° C. for 16 h. After cooling to room temperature the mixture was partitioned between water (50 mL) and ether (50 mL), the aqueous layer being extracted with ether (50 mL). The combined organic extracts were washed with water (50 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography [SiO2; 9:1 (pentane/EtOAc)], then triturated with ether, to give the product (1.1 g, 62%) as a pale yellow solid; δH (CDCl3, 400 MHz) 3.28 (2H, t), 3.41 (2H, t), 6.78 (1H, d), 6.84 (1H, d), 6.92 (1H, s), 7.20 (1H, d), 7.58 (1H, d), 8.00 (1H, s), 10.43 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]O)[CH2:4][CH2:3]1.[BrH:12]>S(=O)(=O)(O)O>[Br:12][CH2:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(CCO)CC1
Reactant: Br
Agent: O=S(=O)(O)O
Product: CC1(C)CCC(CCBr)CC1
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of 2-(4,4-dimethylcyclohexyl)ethanol (WO99/59971) (2 g, 12.8 mmol), concentrated sulphuric acid (750 μl) and 48% hydrobromic acid (3 ml) was stirred at 90° C. for 7 hours. The cooled mixture was then carefully quenched by the addition of water (25 ml), and the mixture was extracted with dichloromethane (3×30 ml). The combined organic extracts were washed with 2M sodium carbonate solution and brine (30 ml), then dried (MgSO4) and concentrated under reduced pressure. The residual black gum was purified by distillation to afford the title compound, 330 mg. 1H-NMR (CDCl3, 400 MHz) δ: 0.82 (2×s, 6H), 1.02-1.20 (m, 4H), 1.35 (m, 3H), 1.50 (m, 2H), 1.78 (m, 2H), 3.40 (t, 2H).
Reaction SMILES: O.[NH3:2].[F:3][C:4]([F:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])[C:5]([F:8])([F:7])[F:6]>C(Cl)Cl>[F:3][C:4]([F:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:2])(=[O:18])=[O:17])[C:5]([F:8])([F:7])[F:6]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F

Procedure:
To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of the crude 2-pentafluoroethoxyphenylsulfonyl chloride obtained in Example 2a, in 50 ml of methylene chloride. After the exothermic reaction has subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yields 65 g of 2-pentafluoroethoxyphenylsulfonamide with a melting point of 145°-146° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:7][C:6]1([CH3:8])[CH2:5][C:4]2([CH3:10])[CH:3]([CH:13]3[CH:12]2[O:11][CH2:16][CH2:15][CH2:14]3)[C:2](=[O:1])[CH2:9]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C1=COCCC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(=O)C2C3CCCOC3C2(C)C1

Procedure:
To a 5-liter round bottomed flask equipped with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 138 g. (1.0 mol.) of isophorone and 498 g. (5.93 mol.) of 3,4-dihydropyran. Enough dichloromethane was added to fill the flask. The solution was bubbled with nitrogen for 1.5 hours and was irradiated with a 450 watt Hanovia medium pressure mercury arc through a Corning 9700 glass filter for 20.5 hours. When the photolysis was completed, the solution was concentrated in vacuo to yield 107.9 g. (0.486 mol.) of a crystalline solid and 80.6 g. of a liquid (0.363 mol.) (Total yield 0.849 mol., 85%). The solid after sublimation and recrystallization had m.p. 111°-112.2° C. IR: 1690 cm-1NMR: (CCl4) 0.92δ (S-3H), 1.12δ (S-3H); 1.32δ (S-3H); 1.35-2.15δ (multiplets 8H); 2.35δ (triplet-2H, J=14Hz); 2.65-2.93δ (M-1H); 3.38-4.20δ (M-2H). The liquid, which had b.p. 101° C./0.3 mm.Hg. was found by glpc to consist of a lower boiling minor component, the solid and a higher boiling product. Redistillation of this fraction gave a fraction, b.p. 85°-90° C./0.1 mm.Hg. which had a NMR (CCl4) spectrum which had methyl singlets at 0.92δ, 1.03δ, 1.10δ and 1.30δ. The singlet at 1.30δ belonged to the solid component, which made up 34% of the mixture. IR: 1695 cm-1.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[C:12]([CH3:25])[CH:11]=1)(=[O:7])[CH3:6].[CH3:26]O>>[C:5]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:26])=[O:23])=[CH:18][CH:17]=2)=[C:12]([CH3:25])[CH:11]=1)(=[O:7])[CH3:6]
Reactant: CO
Reactant: CC(=O)NCc1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(CNC(C)=O)cc2C)cc1

Procedure:
Thionyl chloride (0.119 ml, 1.63 mmol) was added dropwise to MeOH (5 ml) at 0° C., followed by a solution of 4'-acetamidomethyl-2'-methylbiphenyl-4-carboxylic acid (D1, 0.345 g, 1.22 mmol) in MeOH (10 ml). The mixture was heated under reflux for 1.5 hr and the solvent removed in vacuo. The residue was dissolved in CH2 Cl2 (30 ml) and washed with aq. Na2CO3 followed by water. The organic extract was dried (Na2SO4) and concentrated in vacuo to give a colourless oil which purified by column chromatography on silica gel eluting with EtOAc to give a colourless oil that crystallised on standing (0.242 g, 68%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>C1COCC1>[N:12]1([C:6](=[O:10])[C:7]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:8])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(=O)n1ccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
58.5 g (0.79 mol) of tert-butanol are added with stirring at 0° C. under argon to 100 g (0.79 mol) of oxalyl chloride in 1.3 l of THF. After stirring at 0° C for 1 hour, 161 g (2.37 mol) of imidazole in 0.7 l of THF are added dropwise in the course of 60 min. After a further 15 min, the mixture is filtered, the solid is washed with 0.5 l of THF, and the filtrate is concentrated to a volume of 1 l, filtered again, then completely concentrated, allowed to stand overnight at 0° C. under argon and again filtered through a frit.